Elisavet Moutzouri

Comparison of the effects of simvastatin vs. rosuvastatin vs. simvastatin/ezetimibe on parameters of insulin resistance.

Background:  Statin treatment may be associated with adverse effects on glucose metabolism. Whether this is a class effect is not known. In contrast, ezetimibe monotherapy may beneficially affect insulin sensitivity.

Management of dyslipidemias with fibrates, alone and in combination with statins: role of delayed-release fenofibric acid

Cardiovascular disease (CVD) represents the leading cause of mortality worldwide. Lifestyle modifications, along with low-density lipoprotein cholesterol (LDL-C) reduction, remain the highest priorities in CVD risk management. Among lipid-lowering agents, statins are most effective in LDL-C reduction and have demonstrated incremental benefits in CVD risk reduction. However, in light of the residual CVD risk, even after LDL-C targets are achieved, there is an unmet clinical need for additional measures. Fibrates are well known for their beneficial effects in triglycerides, high-density lipoprotein cholesterol (HDL-C), and LDL-C subspecies modulation. Fenofibrate is the most commonly used fibric acid derivative, exerts beneficial effects in several lipid and nonlipid parameters, and is considered the most suitable fibrate to combine with a statin. However, in clinical practice this combination raises concerns about safety. ABT-335 (fenofibric acid, Trilipix®) is the newest formulation designed to overcome the drawbacks of older fibrates, particularly in terms of pharmacokinetic properties. It has been extensively evaluated both as monotherapy and in combination with atorvastatin, rosuvastatin, and simvastatin in a large number of patients with mixed dyslipidemia for up to 2 years and appears to be a safe and effective option in the management of dyslipidemia.

Comparison of the effect of simvastatin versus simvastatin/ezetimibe versus rosuvastatin on markers of inflammation and oxidative stress in subjects with hypercholesterolemia

OBJECTIVES Statins may exhibit anti-inflammatory and antioxidant effects. Whether different statins at equivalent doses or the combination of low-dose statin with ezetimibe have comparable anti-inflammatory and antioxidant effects is unknown. The aim of this study was to compare the effects of simvastatin, simvastatin/ezetimibe or rosuvastatin at equivalent low-density lipoprotein cholesterol lowering doses on inflammation and oxidative stress indices in subjects with hypercholesterolemia. METHODS This was a pre-specified analysis of a prospective, randomized, open-label, blinded endpoint (PROBE) study. We enrolled one hundred and fifty three (n = 153) hypercholesterolemic subjects who were randomized to receive simvastatin 40 mg or simvastatin/ezetimibe 10/10 mg or rosuvastatin 10 mg daily. Plasma 8-Epi prostaglandin F2 alpha (8-epiPGF2a), oxidized LDL (oxLDL) and lipoprotein-associated phospholipase A2 (Lp-PLA2) activity and mass were measured at baseline and following 12 weeks of treatment. RESULTS A significant reduction in plasma 8-isoprostane and oxLDL levels was observed in all treatment groups [by 10%, 8% and 6% (p < 0.05 compared with baseline) and 41%, 40% and 39% (p < 0.001 compared with baseline) in simvastatin, simvastatin/ezetimibe and rosuvastatin groups, respectively]. In all treatment groups a significant reduction in total plasma Lp-PLA2 activity and mass was observed (by 36%, 31% and 38% and 36%, 32% and 32% for simvastatin, simvastatin/ezetimibe and rosuvastatin, respectively, p < 0.001 compared with baseline). No intergroup differences were observed. CONCLUSIONS Simvastatin 40 mg, simvastatin/ezetimibe 10/10 mg and rosuvastatin 10 mg significantly reduced 8-epiPGF2a, oxLDL and Lp-PLA2 activity and mass to a similar extent.

Effect of simvastatin or its combination with ezetimibe on Toll-like receptor expression and lipopolysaccharide - induced cytokine production in monocytes of hypercholesterolemic patients.

OBJECTIVES Toll-like receptors (TLRs) are key players in the innate immune system. Recently, a pivotal role of TLR2 and TLR4 has been recognized in atherogenesis. We investigated the effect of simvastatin monotherapy or its combination with ezetimibe on TLR2 and TLR4 membrane expression and on lipopolysaccharide (LPS)-induced interleukin-1β (IL-1β) and interleukin-6 (IL-6) production in peripheral blood monocytes of patients with primary hypercholesterolemia. METHODS This was a prospective, randomized, open-label, blinded endpoint study. After a 3-month period of lifestyle changes patients (n = 60) (mean age 55 ± 13) with LDL-cholesterol levels above those recommended by the NCEP ATP III, were randomly allocated to open-label simvastatin 40 mg (n = 30) or simvastatin/ezetimibe 10/10 mg (n = 30) daily. Both groups were similar with regard to demographics, risk factors, medications and baseline lipid values. TLR2 and TLR4 membrane expression in monocytes, LPS-induced intracellular production of IL-1β and IL-6 were assessed by flow cytometry at baseline and 3 months post-treatment in both patient groups, as well as in 30 age- and sex-matched normolipidemic controls. RESULTS Hypercholesterolemic patients exhibited higher TLR2 and TLR4 membrane expression compared with controls (p < 0.02). LPS induced a significant increase in the intracellular levels of IL-1β and IL-6 in all groups however both patient groups exhibited significantly lower levels compared with controls. Three months of treatment with either simvastatin or its combination with ezetimibe resulted in a significant reduction of TLR2 and TLR4 expression (p < 0.01 compared with baseline values) with no intergroup differences. Furthermore, in both groups the post-treatment values of LPS-induced IL-1β and IL-6 production were significantly lower compared with baseline (p < 0.05 for all comparisons). CONCLUSIONS A high simvastatin dose or the combination of a low-dose simvastatin with ezetimibe reduce to a similar extent TLR2, TLR4 membrane expression and LPS-induced IL-6 and IL-1β production in monocytes of hypercholesterolemic patients. The pathophysiological significance of these effects regarding atherosclerosis, reserves further investigation.

The effect of simvastatin alone versus simvastatin plus ezetimibe on the concentration of small dense low-density lipoprotein cholesterol in subjects with primary hypercholesterolemia

Abstract Objective: To compare the effects of simvastatin alone versus simvastatin plus ezetimibe on small dense low-density lipoprotein cholesterol (sdLDL-C) concentration in subjects with primary hypercholesterolemia. Research design and methods: Patients with LDL-C levels above those recommended by the National Cholesterol Education Program Adult Treatment Panel III were randomized to open-label simvastatin 40 mg (n = 50) or simvastatin/ezetimibe 10/10 mg as a fixed combination (n = 50) daily. LDL particle size (estimated by electrophoresis), sdLDL-C levels, and lipid profile were blindly assessed at baseline and 3 months. Clinical trial registration: clinicaltrials.gov NCT00932620. Results: Both simvastatin 40 mg and simvastatin/ezetimibe 10/10 mg decreased total cholesterol (−31% and −36%, respectively), LDL-C (−43% and −49%, respectively), triglycerides (−17% and −19%, respectively), non-high-density lipoprotein cholesterol (non-HDL-C; −40% and −46%, respectively), large LDL-C (−40 and −44%, respectively) and sdLDL-C levels (−42% and −46%, respectively, all p < 0.000 vs baseline) and increased LDL particle size (+0.5% and +0.7%, respectively, both p < 0.05 vs baseline). The changes in total cholesterol, LDL-C and non‐HDL-C were greater in the simvastatin/ezetimibe group (all p < 0.05). Changes in triglycerides, large LDL-C, sdLDL-C levels and LDL particle size were similar in the two groups. In multivariate analysis, baseline sdLDL-C and triglyceride levels, but not the choice of treatment, were significantly and independently correlated with the changes in sdLDL-C levels. Conclusion: The combination of simvastatin 10 mg plus ezetimibe 10 mg is similarly effective to simvastatin 40 mg in improving sdLDL-C concentration and LDL particle size in subjects with primary hypercholesterolemia.

Prediabetes: to treat or not to treat?

The incidence of diabetes is continuously increasing worldwide. Pre-diabetes (defined as impaired glucose tolerance, impaired fasting glucose or both) represents an intermediate state, which often progresses to overt diabetes within a few years. In addition, pre-diabetes may be associated with increased risk of microvascular and macrovascular complications. Thus, reverting a pre-diabetic state as well as preventing the development of diabetes represents enormous challenge for the clinician. Lifestyle modification in pre-diabetic individuals was found particularly effective in the prevention of diabetes. However, compliance to lifestyle modification measures can be a crucial problem in the everyday clinical practice, especially in developing countries. During the last decade many studies support the use of anti-diabetic treatment schemes in pre-diabetic subjects to be advantageous. The American Diabetes Prevention Program (DPP) as well as other minor studies and meta-analyses has convincingly demonstrated the efficacy of metformin in this patient group. In addition, results of the 10 year DPP follow up have recently been published, demonstrating the long term safety and sustainability of metformin treatment benefits in this population. In contrast to metformin, the evidence from the use of other anti-diabetic agents (thiazolidinediones, a-glucosidase inhibitors, incretin mimetics) in pre-diabetic individuals is rather inadequate and prospective data is further needed. Furthermore, large scale studies with hard clinical endpoints are needed to delineate the effect of pre-diabetes treatment on macro- and microvascular complications. In conclusion, several strategies of patient management, mainly lifestyle modification and pharmacological interventions can prevent diabetes development in subjects diagnosed with pre-diabetes or even revert pre-diabetic state. However, whether this biochemical improvement can be translated into actual clinical benefit remains to be established.

Effect of Simvastatin/Ezetimibe 10/10 mg Versus Simvastatin 40 mg on Serum Vitamin D Levels

Backround: Low levels of 25-hydroxyvitamin D (25(OH)VitD) have been recognized as an emerging cardiovascular disease (CVD) risk factor. Statins are reported to increase 25(OH)VitD concentration. Animal studies suggest that ezetimibe is a moderate inhibitor of intestinal 25(OH)VitD absorption, but its effect in humans is unknown. Aim: To investigate whether combined treatment with simvastatin/ezetimibe 10/10 mg would increase 25(OH)VitD levels compared to simvastatin 40 mg monotherapy in patients with primary hypercholesterolemia. Methods: In a Prospective Randomized Open-label Blinded End point study, 50 patients with primary hypercholesterolemia received either simvastatin/ezetimibe 10/10 mg (n = 25) or simvastatin 40 mg (n = 25) daily for 3 months. The primary end point was between-group difference in the change of serum 25(OH)VitD levels. Results: Simvastatin/ezetimibe 10/10 mg was associated with a 36.7% increase in 25(OH)VitD serum levels (from 6.8 to 9.3 ng/mL, P = .000), while simvastatin 40 mg was associated with a 79.1% increase (from 6.7 to 12.0 ng/mL, P = .008). The increase in 25(OH)VitD levels in the simvastatin 40 mg group was significantly greater compared to that in the simvastatin/ezetimibe 10/10 mg group (P = .04). Both groups exhibited similar reductions in low-density lipoprotein cholesterol (LDL-C) levels. Conclusion: For similar LDL-C lowering simvastatin 40 mg is associated with greater increase in 25(OH)VitD compared to simvastatin/ezetimibe 10/10 mg. Whether this difference is relevant in terms of CVD risk reduction is unknown.

Effects of Statin Monotherapy Versus Statin Plus Ezetimibe Combination on Serum Uric Acid Levels

Background: Uric acid is considered a risk factor for cardiovascular disease (CVD). The effect of statins and ezetimibe on serum uric acid levels has not been yet clarified. Objective: To compare the effect of simvastatin/ezetimibe 10/10 mg, simvastatin 40 mg, and rosuvastatin 10 mg daily on serum uric acid levels in patients with dyslipidemia. Methods: This was a prospective, randomized, open-label, blinded end point (PROBE) study. Following a 3-month dietary intervention, patients with hypercholesterolemia received simvastatin/ezetimibe 10/10 mg or simvastatin 40 mg or rosuvastatin 10 mg. Changes in serum levels of uric acid and fractional renal excretion of uric acid as well as changes in electrolyte and renal function parameters were assessed after 12 weeks of treatment. Results: One hundred fifty-three patients (56 male) were included. At week 12, a significant reduction in serum uric acid levels was seen in all treatment groups (simvastatin/ezetimibe 10/10 mg: −3.8%, simvastatin 40 mg: −5.7%, and rosuvastatin 10 mg: −3.8%; P < .05 compared with baseline; P = not significant [NS] for comparison between groups). Fractional excretion of uric acid nonsignificantly increased in all groups (simvastatin/ezetimibe 10/10 mg: +6.8%, simvastatin 40 mg: +6.8%, and rosuvastatin 10 mg: +5.9%). The reduction in serum uric acid levels correlated with the increase in fractional excretion of uric acid and baseline uric acid levels. Renal function parameters as well as serum levels and fractional excretions of electrolytes remained unchanged in all groups. Changes in serum lipids were similar across groups. Conclusion: Simvastatin/ezetimibe 10/10 mg, simvastatin 40 mg, and rosuvastatin 10 mg exhibit a similar uric acid–lowering effect.

Aliskiren, a Direct Renin Inhibitor, in Clinical Practice: A New Approach in the Treatment of Hypertension

OBJECTIVE Arterial hypertension is an important risk factor for the development and progression of cardiovascular disease (CVD). The renin angiotensin aldosterone system (RAAS) plays a crucial role in the pathophysiology of hypertension and associated complications. Direct renin inhibitors (DRIs) are novel antihypertensive drugs which inhibit the first step of RAAS. Aliskiren is the first orally active DRI approved as monotherapy or in combination with other antihypertensive agents for the treatment of hypertension. SCOPE This article reviews the efficacy and safety of aliskiren as monotherapy and in combination with other antihypertensive agents and comments on its potential role in clinical practice. METHODS Relevant articles were identified through a PubMed search (up to 17 August 2009). FINDINGS Aliskiren, used alone or in combination with other antihypertensive agents, has a favourable effect on blood pressure (BP). Specifically, aliskiren is equally effective with other RAAS inhibitors and probably superior to hydrochlorothiazide in the reduction of systolic and diastolic BP. The combination of aliskiren with other antihypertensive drugs seems to be an effective and safe therapeutic option. In addition, aliskiren may have favourable effects in terms of ameliorating several microvascular and macrovascular complications of hypertension and diabetes. CONCLUSIONS Aliskiren appears to be an effective and safe antihypertensive drug. Whether the BP lowering effect of aliskiren is associated with improvements in cardiovascular outcomes remains to be elucidated.

Inflammatory biomarkers and cardiovascular risk assessment. Current knowledge and future perspectives.

Cardiovascular disease is the leading cause of morbidity and mortality in the Western world. However, it appears that currently available risk assessment tools often underestimate risk, especially for patients in the intermediate-risk category. Considering the socioeconomic cost, it is imperative to correctly identify patients in the intermediate-risk category who would benefit from more aggressive treatment. A plethora of experimental and observational studies provide support that lipoprotein associated phospholipase A2 (Lp- PLA2) and secretory phospholipases A2 (sPLA2)) as well as high sensitivity C-reactive protein (hsCRP) are useful biomarkers of cardiovascular risk. Particularly, Lp-PLA2) has also been addressed as pharmacological target and we are eagerly awaiting the results of ongoing phase III clinical trials. In this review we discuss the current literature regarding the pros and cons of these biomarkers.